CHEMOTHERAPHY

The use of specific chemical compounds
to combat spe­cific human ailments has long been the goal of the biochemist.
The Incas of Peru had early hit upon cinchona bark extract for relief against
malaria, and by 1639 this “quinine” was introduced into Europe. Though only
partially effective it gave abundant indication of the manner in which certain
chemicals may serve as specifics. Somewhat later this dreaded malaria, resulting
from infection with the protozoan Plasmodia as trans­mitted by the female
of the Anopheles mosquito, was brought up against two synthetic antimalarials—Schule­mann’s
“Plasmochin” of quinoline base in 1926, and “Atebrin” of acridine base in
1930 by Mauss and Mietzsch, all from the I. G. Farbenindustrie laboratories.

But practically speaking, chemotherapy had its incep­tion
in the work of Ehrlich. In the application of various dyes for staining tissues
Ehrlich, in 1907, modified benzopurpurin into an azo dye, Trypan Red, and
found it effective in mice against trypanosome parasites— thereby constituting
the first synthetic chemotherapeutic agent. Thus Ehrlich came to describe
chemotherapeutic agents as possessing various degrees of specificity against
protozoal and bacterial invaders in animals without injury to the host. The
appearance of Ehrlich’s “arsphena­mine” (Salvarsan) in1910 marks the beginning
of a new day in Medicine.

In 1913 Eisenberg
discovered that the azo dye Chrysoidine (2,4-diamino azobenzene) was bactericidal
in vitro;on December 25, 1932, Mietzsch and Klarer of I.G. Farbenindustrie
were granted a German Patent on Sulfonamido-chrysoidine or Prontosil.In 1932 Gerhard Domagk of the Institute of Experimental Pathology of
I.G. Farbenindustrie at Elberfeld, Germany, proved that Prontosil was relatively
nontoxic yet protected mice against hemolytic streptococcal infections—in
fact his experiments were perfect: 100 percent of the mice infected came through
alive. Strangely enough, Domagk showed that Prontosil displayed no bactericidal
action in vitro—toquote him: “It acts as a true chemothera­peutic
agent only in the living animal.” The announce­ment of these discoveries was
not made until February 15, 1935.

Next in turn the French took up the problem
of ascertaining what part of Prontosil carried the effective group. Mr. and
Mme. Trefouël, Nitto and Bovet at the Pasteur Institute in Paris soon reported
that Prontosil underwent a dissociation in animal tissues to yield para­amino
benzene sulfonamide. Whereupon Professor Fournenu of the same Institute prepared
pure p-amino benzene sulfonamide (sulfanilamide) and tested it against streptococcal
infections in mice and rabbits and found it just as effective as Prontosil,
thus proving that the double-nitrogen or azo linkage (the dye-forming linkage)
possessed no therapeutical value.

In England, Buttle, Gray,
and Stephenson, in Lancet for June 6, 1936, confirmed the results of
the French Scientists and undertook the synthesis of a large number of derivatives
of the active p-amino benzene sulfonamide.

Eventually American biochemists awoke to the significance
of this new synthetic. Drs. Perrin H. Long and Eleanor A. Bliss of Johns Hopkins
Medical School led the way to far-reaching researches in this field. The first
publication in this country was of January 2, 1937, in the Journal of the
American Medical Association.

From the Lederle Laboratories
came the announce­ment last year of a new sulfa drug called Phenosulfazole.This new drug, known also as Darvisul, has proved to be effective against
poliomyelitis in mice and is now under test on humans at Columbia University.

The remarkable results securable by sulfanilamide
against modern scourges may be measured by the reduc­tion of pneumonia fatalities
from 30 percent a decade ago to less than 10 percent today. The entire gamut
of sulfanilamides is now known to interfere with the nu­trition of bacteria
setting up a virtual bacteriostasis. As bacteria require p-amino benzoic acid,
a factor in the vitamin B complex, they are confronted here with a closely
analogous structure, and when once fixed by sul­fanilamides, have no other
recourse than starvation.

Likewise these sulfa compounds, as well as thiourea and thiobarbituric
acid, serve as antihormone drugs inhibiting production of thyroxine because
of their close structural relationship to the amino acid tyrosine, the precursor
of thyroxine, thereby interfering with the enzyme system called upon for production
of this thy­roxine. Furthermore, this close analogy between sulfa antivitamin
and antihormone compounds may indicate that hormone like carcinogens may,
in their turn, actually interfere with normal metabolism under some particular
cellular enzyme systems and thus make possible the metamorphosis of a normal
cell into a cancer cell. Even vitamin D, which is a dehydrocholesterol closely
similar to a sex hormone, can be pictured as one possible of such diversion.

As far back as 1877 Pasteur and. Joubert announced that certain
airborne organisms were found to interfere with the growth of the anthrax
bacillus; indeed they intimated that some day this phenomenon of antibiosis
might be brought under such control as to be of value in treatment of infection.
Today microorganisms are known to produce any number of chemical entities
capable of combating the growth of other organisms. Hence the entree of antibiotics
into the realm of chemotherapy.

To Alexander Fleming, of St. Mary’s Hospital in Lon­don, goes
the honor of being first to observe the destruction of bacteria by blood leucocytes
concentrating in pus of wounds studied during World War I. His report in 1929
on the destruction of certain staphylococcal colonies on slides accidentally
subjected to traces of mold growth prepared the way for extraction of this
mold, Penicillium notatum Westling, to secure the active principle, penicillin;
furthermore, Fleming was able to show that penicillin was nontoxic to animals
and even to leucocytes.

As reported in 1940 by Lancet, Howard W. Florey
and his colleagues, of the Sir William Dunn School of Pathology in Oxford,
England, had the honor of bringing penicillin to the foremost position among
antibiotics. Within a year penicillin had been purified and brought into systematic
use for the treatment of infection. The action of penicillin is essentially
bacteriostatic against both streptococci and staphylococci, and in many instances
in as low a concentration as 1 part in 32,000,000 of water—a far greater activity
than that reported for sulfa drugs. Thus penicillin came into the role of
an ideal therapeutic agent, and particularly so by reason of its effectiveness
in the treatment of wounds by local applications. However, whether administered
intrave­nously or intramuscularly, or even by mouth, this antibi­otic passes
out of the system in the course of three to four hours.

PENICILLIN

Naturally the story of penicillin opened up the study of a vast
array of microscopic forms oflife, both pathogenic and saprophytic.
From acid soils we had need to study fungi; from dry and alkaline soils we
had need to study actinomycetes; from all soils the study of bacteria—aero­bic
bacteria of sandy, aerated soils and anaerobic bacteria of waterlogged and
peaty soils; with a study of protozoal life everywhere. Generally speaking,
an extensive root system of growing plants bespeaks highest aeration.In all of this it must not be overlooked that
the presence of trace elements and growth-promoting vitamins plays an all-important
role in the nutrition of microorganisms. There is no doubt but that these
antibiotic agents func­tion as parts of enzyme systems, such systems being
en­abled to dissolve away or destroy the capsular material ordinarily protecting
bacteria and thereby exposing the latter to the leukocytes of the blood stream.

The resolution of Prontosil of dye like structure into a far simpler
type—Para-aminobenzene sulfonamide, or sulfanilamide—is thoroughly elucidative
of what may be expected in the entire realm of chemotherapeutic agents. The
simpler structures not only carry the effective agency but also are far less
likely to undergo disintegration by body fluids. Penicillin will no doubt
yield to centralization of its active residue. Already it is reported* that
the effec­tiveness of penicillin against certain bacteria has been quadrupled
by the addition of a mere trace of cobalt chloride. Among the other antibiotics
from fungi, quite a few hark back in structure to just plain Parabenzo­quinone,
than which few antibiotics are more active.

(* Journal of the American Pharmaceutical Association, 37,
133, April 1948.)

A striking advance among antibiotics is that of Chloromycetin,
discovered by Dr. Paul R. Burkholder of Yale University while studying soil
from Venezuela. The mold yielding this antibiotic is known as Streptomyces
venezuelae.

The antibiotic itself is effective against scrub typhus, typhoid,
Rocky Mountain, and undulant fevers. Synthesis of this antibiotic was accomplished
in 1948 by Harry M. Crooks, Jr., Mildred C. Rebstock, and John Controulis
of Parke, Davis & Company. The synthetic product has been named “Chloramphenicol.”
In the formula assigned it will be observed that the presence of a nitro group
(NO2) and several chlorine atoms (Cl) are apparently without toxic
effect—something exceptional in the course of therapeutic compounds. Only
one of the four possible optical isomers displays antibiotic activity.

Space
forbids too extensive enumeration of all the antibiotics under study in recent
years; yet one recently discovered is of far reaching promise against tuberculosis.
This is streptomycin, isolated in 1944 from Streptomyces griseus (of
certain soils) by Dr. Selman A. Waksman and his colleagues at Rutgers University.
Streptomycin presents a chemical configuration based upon inositol, the chief
component of corn “steep-water.” This structure, elucidated in 1943 by Kuehl,
Peck, Hoffhine, and Folkers of the Merck Laboratories, involves the indi­vidual
replacement of each of two hydroxyl substituents in inositol by the guanidyl
group, —NH-C(NH2)NH (imino-urea), and a third hydroxyl substituent
tied into a specific disaccharide (or sugar type) group:

As far as is now known, the keto group (CO) or
the thionyl group (SO) is common to all antibiotics, usually in juxtaposition
to a carbon atom carrying a labile hy­drogen, or preferably to a carbon atom
carrying likewise an oxygen atom (a keto group); this latter grouping constituting
what is called a “conjugated system.” In the human body amino acid oxidizes,
previously mentioned as universally present, are most effective in transamina­tion,
wherein an oxygen atom will replace the hydrogen and guanidyl group on each
of two carbon atoms of the inositol ring of streptomycin. Thus will arise
a strepto­mycin carrying two keto groups, in place of the two-guanidyl groups,
and thereby serving as an oxidant still carrying the disaccharide group. Yet
here again a further dehydrogenation through the action of the aldehyde group
of the disaccharide group present might well lead to a dihydroxy tetraketobenzene
(rhodizonic acid) directly after the splitting away of the disaccharide group.
Eventually we can expect an end product of hexa­ketocyclohexane (triquinoyl),
of six keto or carbonyl groups in a ring.

Naturally
we cannot avoid coming to the inference that possibly the organic chemist
can supply the world with just those compounds ideally suited to each and
every type of infection. Much of this we even now pro­claim is within the
bounds of synthetic organic chemistry. Starting back in 1918, Dr. William
F. Koch of Detroit, now of Rio de Janeiro, Brazil, began his ex­periments
striking at the heart of immunity. He em­ployed Parabenzoquinone in extremely
dilute solutions (one to a million) and in­jected two cc. of said solution
into the patient intra­muscularly.

His treatment
of mastitis in cows has sur­passed highest expectations. Notably among humans
many cases suffering from tuberculosis yielded readily to treatment with this
quinone, thereby proving that the quinone was serving as an oxygen carrier
and exerting a high healing effect directly in the neighborhood where oxygen
was inhaled by the individual. How much more likely, then, is the action of
rhodizonic acid, of higher keto content, by way of streptomycin, to register
itself as beneficial in treatment of tuberculosis!

Recent clinical reports from Mount Sinai Hospital, New
York City, confirm the effect of certain keto compounds (among them rhodizonic
acid) on reduction in blood pressure of hypertensive rats, and yet without
disturbance to the blood pressure of normal rats.

But if the inositol ring can function so advantageously
when dehydrogenated into rhodizonic acid, what should we expect of a further
dehydrogenation—say, carried to completion; i.e., into hexaketocyclohexane
or triquinoyl?

In practice triquinoyl has been found to act almost
identically with “Glyoxylide” (O=C=C=O), a compound that Dr. Koch bad prepared
by dehydration of glyoxylic acid (CHO-COOH). In brief, this so-called Glyoxylide,
which has proved so efficacious in the hands of Dr. Koch against diabetes,
arthritis, poliomyelitis, and even cancer, undoubtedly polymerizes under many
conditions to 3(O=C=C=O) or triquinoyl, in which an oxygen atom is doubly
linked to each of the six carbon atoms of the reduced (or saturated) benzene
ring carbon structure, and plays a most effective role in the treatment of
disease. In the likely dehydrogenation of inositol within the body we can
now interpret the phenomenal action of inositol in replacing insulin for diabetics.

Thus when the valuable streptomycin is shorn of its
disaccharide substituent, as well as guanidyl substituents, it becomes a simple
compound of high oxidative poten­tial and of highest efficacy in the treatment
of disease. The most active end product, triquinoyl, constitutes a virtual
super-streptomycin. But it does not constitute only a super-streptomycin;
it constitutes a superpenicillin and superantibiotic in general.

Of outstanding effect here is the extreme dilution at which
these antibiotic agents appear to function best. No one ever dreamed of such
dilutions until penicillin made its entrance upon the stage of medicine, and
here 1 part to 32,000,000 is nothing out of the ordinary.Dr. Koch merely stepped up this
dilution some thousandfold when ideal results were found to arise. Of course,
criticism emanating from unschooled biochemists scoffed at such dilutions:
Ultimate analyses proved totally incapable of revealing the presence of the
compounds used; and so they should. Only by application of radioactive tech­nique
can the presence of such compounds in such high dilutions be detected. Yet
in a dose of triquinoyl of 2 cc’s in the dilution of 1:1,000,000,000, these
2 cc’s introduce into the system the amazing number of more than 5,000,000,000,000
molecules of the active agent! Only so recently as in Science Illustrated
for February 1947 is it reported that Professor Gilbert M. Smith, at StanfordUniversity, was able to affect a metamorphosis of the cells of a microscopic
plant from the sessile, or asexual phase, to the actively motile, mate-seeking
sexual cells, by the application of one part of crocetin (C13H22
(COOH) 2) in 250 trillion parts of water!

Now the role
of these polyketocompounds is definitely oxidative. By their presence a higher
level of metabolism is made possible in the system, and, like a passing wave
over a golden wheat field, this wave of oxidative influ­ence continues unabated
for months upon months— sufficient, indeed, to heal improperly nourished organs
and slough off decadent tissues. All of this is in accord­ance with findings
of H. Wieland proving first the hydra­tion of an active carbonyl group in
body fluids into =C=(OH)2 and its subsequent dehydrogenation by
en­zymes into a peroxide type, =C=O=O, whereupon nascent oxygen is liberated
and the carbonyl group (=C=O) regenerated to repeat the process. Just as Pasteur
identi­fied the microscopic organisms that led to plant disease, so Koch identifies
the chemical agents that are capable of combating microorganisms.

In Brazil this
new interpretation of immunity is meeting with wholehearted cooperation on
the part of the government.Happily
the Brazilian authorities are sufficiently open-minded to recognize that the
cure for many diseases, when once established, will prove to be an oxidant
capable of restoring normal functions in cell growth.In this country many able physicians are applying the carbonyl therapy,
notably Dr. Edwin D. MacKinnon of Saginaw, Michigan, and Dr. George W. Palm
of Prudenville and Detroit, Michigan.There
is no more interesting presentation on this subject by a physician than that
published by the late Dr. Albert L. Wahl of Mount Vision, New York. This brochure
is entitled A Least Common Denominator in Antibiotics.

Intelligence
Digest* has recently published a short account of the remarkable curative
properties of H.11 against cancer. This H.11 is prepared by the Hosa Research
Laboratories Windmill Road, Sunbury-on-Thames of London, England, and is an
oxidant similar to the Koch compounds in structure.

Highly germane to the program of stepped-up oxidative
processes within the human system is the absolute necessity for careful selection
of proper foods to accom­pany these treatments. In fact, it is generally stated
that half of the treatment lies in the diet. Thus highly reduc­tive agents
contained in foods and medicines must be shunned.

For perfect health there is only one correct course to follow:
the selection of those foods that carry the whole gamut of vitamins and amino
acids and. trace elements. It thus becomes necessary to learn something of
the agricultural areas on which our fruits, grains, and vegetables are grown
if we are to be assured of the proper nutrient. Meats, of course, will now
and then need to be selected; but as time passes, the requirements for meat
will fade away in the light of synthetic supply of the required amino acids
and proteins. Above all, our foods must carry a sufficient supply of oxidants
to main­tain metabolism at its highest level. These oxidants are ever present
in the coverings of seeds and tubers; they are not present in highly refined
foods. Old age comes upon us primarily by reason of the absence of these oxidants.
With oxidants in full supply, the digestion of foods proceeds normally and
the wear and tear on our blood vessels is reduced to a minimum.